In vitro, glutamine reduced the frequency of doxorubicin-induced chromosomal aberrations (Tavares et al. 1998). In rats, treatment with glutamine before and during doxorubicin administration diminished the cardiotoxic effects of the drug by upregulating glutathione synthesis in the heart (Cao et al. 1999). Clinically, treatment with glutamine (4 g bid) and doxorubicin reduced the incidence and severity of mucositis relative to prior experience with chemotherapy (Skubitz and Anderson 1996).

Chemotoxic effects were absent in 9 breast cancer patients treated with glutamine (0.5 g/kg/day) during therapy with escalating doses of methotrexate followed by doxorubicin; the median survival of participants was 35 months (Rouse et al. 1995). Preclinical and clinical studies have demonstrated that glutamine enhances the activity and tumor-selectivity of methotrexate therapy, while actively protecting normal tissues. In rats, glutamine (1 gm/kg/day po) and an intraperitoneal dose of methotrexate (20 mg/kg) increased the concentration of the drug in tumors threefold (Rubio et al. 1998). Supplemental glutamine also increased the therapeutic index for methotrexate by enhancing glutathione synthesis systemically, thus improving drug tolerance while simultaneously depleting tumor glutathione in rats (Rouse et al. 1995). In addition, rats fed a glutamine-supplemented diet (3%) had decreased clearance and urinary excretion of methotrexate by 25% and 65%, respectively (Charland et al. 1995).

Whether glutamine supplementation is beneficial during treatment with 5-fluorouracil appears to be questionable. In two placebo-controlled trials involving several patients, oral glutamine supplementation did not have a significant effect on 5-FU-induced mucositis (Jebb et al. 1994; Okuno et al. 1999). However, in another trial, glutamine (glycyl-L-glutamine) did reduce indices of ulcerations in the gastric and duodenal mucosae significantly (Decker-Baumann and Buhl 1999).

Cao Y, Kennedy R, Klimberg VS. Glutamine protects against doxorubicin-induced cardiotoxicity. J Surg Res. 1999;85:178-182.

Charland SL, Bartlett DL, Torosian MH. A significant methotrexate-glutamine pharmacokinetic interaction. Nutr. 1995;11:154-158.

Decker-Baumann C, Buhl K. Reduction of chemotherapy-induced side-effects by parenteral glutamine supplementation in patients with metastatic colorectal cancer. Eur J Cancer. 1999;35:202-207.

Jebb SA, Osborne RJ, Maughan TS. 5-fluorouracil and folinic acid-induced mucositis: no effect of oral glutamine supplementation. Br J Cancer. 1994;70: 732-735.

Okuno SH, Woodhouse CO, Loprinzi CL. Phase III controlled evaluation of glutamine for decreasing stomatitis in patients receiving fluorouracil (5-FU)-based chemotherapy. Am J Clin Oncol. 1999;22:258-261.

Rouse K, Nwokedi E, Woodliff JE, et al. Glutamine enhances selectivity of chemotherapy through changes in glutathione metabolism. Ann Surg. 1995;221: 420-426.

Rubio IT, Cao Y, Hutchins LF, et al. Effect of glutamine on methotrexate efficacy and toxicity. Ann Surg. 1998;227:772-780.

Skubitz KM, Anderson PM. Oral glutamine to prevent chemotherapy induced stomatitis: a pilot study. J Lab Clin Med. 1996;127:223-228.

Tavares DC, Cecchi AO, Antunes LM, et al. Protective effects of the amino acid glutamine and of ascorbic acid against chromosomal damage induced by doxorubicin in mammalian cells. Teratog Carcinog Mutagen. 1998;18:153-161.